HOMA-IR increase after antidepressant treatment in depressed patients with the Met allele of the Val66Met BDNF genetic polymorphism.

BACKGROUND: The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with response to antidepressant drugs in depressed patients and with metabolic side effects after antipsychotic treatment. This study aims to assess the association between this polymorphism and insulin resistance after antidepressant treatment in depressed patients. METHODS: One hundred forty-eight Caucasian patients with a current unipolar major depressive episode (DSM IV-TR) were genotyped for the BDNF Val66Met polymorphism and assessed at baseline and after 3 and 6 months of antidepressant treatment for the 'Homoeostasis model assessment of insulin resistance' (HOMA-IR) index, a valid measure of insulin resistance based on fasting plasma insulinaemia and glycaemia. Because validity assumptions were fulfilled, data were analysed using analysis of variance for repeated measures. RESULTS: The 52 (35%) Met carriers and 96 (65%) Val/Val patients were not different at baseline for clinical characteristics and HOMA-IR. A significant Val66Met × time interaction (p = 0.02), a significant time effect (p = 0.03) and a significant Val66Met effect (p = 0.0497) were shown for HOMA-IR. A significant Val66Met × time interaction (p = 0.01) and a significant time effect (p = 0.003) were shown for fasting glycaemia. HOMA-IR and fasting glycaemia changes after antidepressant treatment were significantly higher in Met carrier than in Val/Val patients (HOMA-IR changes: Met: 0.71 ± 3.29 v. Val/Val: -0.16 ± 1.34, t = 2.3, df = 146, p = 0.02, glycaemia changes: Met: 0.09 ± 0.30 v. Val/Val: 0.02 ± 0.16, t = -2.0, df = 146, p = 0.045). CONCLUSIONS: The Met allele of the Val66Met BDNF polymorphism confers to depressed patients a higher risk of insulin-resistance after antidepressant treatment. These patients could benefit from specific monitoring of metabolism and preventive measures.

Early weight gain predicts later metabolic syndrome in depressed patients treated with antidepressants: Findings from the METADAP cohort.

BACKGROUND: Metabolic syndrome (MetS) is a major public health issue. We assessed whether early weight gain predicts later MetS in depressed patients treated with antidepressants. METHODS: In the 6-month prospective METADAP cohort, 260 non-overweight patients with a Major Depressive Disorder (MDD) and a current Major Depressive Episode (MDE) were assessed for early weight gain (>5%) after one month of treatment, and for the later incidence of MetS after three and six months of treatment. Outcome variables were MetS, the number of MetS criteria, and each MetS criterion (high Waist Circumference (WC), high Blood Pressure (BP), high triglyceridemia (TG), low HDL-Cholesterolemia, and high Fasting Plasma Glucose (FPG). Multivariate models were adjusted for age, sex, previous MDD duration, severity of current MDE, and antidepressants. RESULTS: 24.6% of patients had early weight gain. Compared to those without weight gain, patients with early weight gain had higher MetS incidence: 16.7% vs. 6.9% after 3 months (p = 0.07), and 23.8% vs. 7.1% after 6 months (p = 0.02). Among completers (n = 120), early weight gain was significantly associated with later MetS incidence (OR: 5.5) and a higher number of MetS criteria (IRR: 1.7). This effect was driven by the WC, TG, and HDL-C criteria. CONCLUSION: Compared to Non-early weight gainers, patients with early weight gain in the first month of antidepressant treatment have a significant higher risk of developing MetS during the 6 months of treatment. Early weight monitoring is recommended in order to set preventive measures to avoid new metabolic syndromes in depressed patients treated with antidepressants.

The TRKB rs2289656 genetic polymorphism is associated with acute suicide attempts in depressed patients: A transversal case control study.

INTRODUCTION: Suicide Attempts (SA) are the main complications of Major Depressive Episodes (MDE) and are difficult to predict. Suicide is associated with the expression of Receptor Tyrosin-Kinase B (TRKB), the receptor of the Brain Derived Neurotrophic Factor (BDNF) involved in MDE. However, the impact of its genetic polymorphisms as predictive factors of SA should be clarified. Our main aim is to assess the association of 8 TRKB genetic polymorphisms and SA in depressed patients. MATERIAL AND METHODS: In 624 patients currently experiencing an MDE in the context of Major Depressive Disorder (MDD) (METADAP study), we assessed the association between 8 TRKB genetic polymorphisms (rs1778933, rs1187352, rs2289658, rs2289657, rs2289656, rs3824519, rs56142442 and rs1439050) and acute (previous month) or past (older than one month) SA. Bonferroni corrections and multivariate analysis adjusted for age, sex, level of education, marital status, Hamilton Depression Rating Scale score and previous MDE were used. RESULTS: The rs2289656 was associated with acute SA (CC = 28.5%, CT = 15.0% and TT = 11.5%, p = 0.0008). However, the other SNPs were not. Patients with the CC genotype had a higher rate of acute SA (28.5%) as compared to T carriers (14.6%) (adjusted OR = 2.2, CI95% [1.4; 3.5], p<0.0001). CONCLUSION: The TRKB rs2289656 CC genotype is associated with a 2.2 fold higher risk of acute SA in depressed patients. If this result could be confirmed, this TRKB SNP may be assessed to contribute to the prediction of SA in depressed patients.

Early weight gain predicts later weight gain in depressed patients treated with antidepressants: Findings from the METADAP cohort.

BACKGROUND: Weight gain is a major side effect of antidepressant (AD) drugs. We assessed whether early weight gain is a predictor for long term weight gain in depressed patients treated with antidepressants. METHODS: In the six month prospective METADAP cohort, 260 non-overweight patients with a major depressive disorder (MDD), who have recently experienced a Major Depressive Episode (MDE) were assessed for early weight gain (>3%,>5%, and >7%) after one month of treatment, and for long term weight gain (>15% and >20%) after three and six months of treatment. ROC analysis was used to determine the predictive power of early weight gain. RESULTS: 12.4% (21/170) of patients became overweight after three months of treatment and 21.1% (26/123) were overweight after six months. Compared to non-early weight gainers, patients with early weight gain (>3%, >5% and >7%) were 11.3 (OR = 11.3, 95%CI: 4.6-27.6)], 9.9 (OR = 9.9, 95%CI: 3.6-26.9)] and 17.8 (OR = 17.8, 95%CI: 6.4-49.4)] times, respectively, more at risk of late weight gain (>15%). ROC analysis showed that early weight gain (>3%) after one month of treatment, was the best predictor of long term weight gain (≥15%) after three months [Area Under the Curve (AUC )= 87%] and six months of treatment (AUC = 88%) PERSPECTIVES: Given that our baseline sample consisted of strictly non-overweight patients, the 3% threshold for weight gain after one month should be used as an indicator to initiate early weight monitoring in depressed patients treated with antidepressants. High attrition rate remains a limitation in this cohort and other cohorts in psychiatric settings. DISCLOSURES: Bruno Falissard consults for and received lecture fees from for E. Lilly, BMS, Servier, Sanofi-Aventis, GlaxoSmithKline, HRA, Roche, Boeringer Ingelheim, Bayer, Almirall, Allergan, Stallergene, Genzyme, Pierre Fabre, Astra Zeneca, Novartis, Janssen, Astellas, Biotronik, Daiichi-Sankyo, Gilead, MSD, Lundbeck. Florence Gressier received lecture fees from for Servier, Lundbeck and a grant from Servier. Mircea Polosan consults for and received lecture fees from Astra-Zeneca, Bristol Myers Squibb, Lundbeck, Otsuka and Servier. Emmanuel Haffen consults for and received lecture fees from Astra-Zeneca, Bristol Myers Squibb, Pfizer, Lilly, Lundbeck, Otsuka, Sanofi-Aventis, Servier. Philippe Chanson has received unrestricted research and educational grants from Ipsen, Novartis, Novo-Nordisk, and Pfizer for the Department of Endocrinology and Reproductive Diseases, Hôpitaux Universitaires Paris-Sud and for INSERM U 693. He has served as investigator (principal or coordinator) for clinical trials funded by Novartis, Pfizer, Ipsen, Italopharmaco, Antisense, Prolor Biotech. He is member of Advisory Boards from Ipsen, Novartis, Viropharma. He gave lectures for Ipsen, Novartis, Pfizer, NovoNordisk. All the fees and honoraria were paid to his Institution. Bruno Falissard consults for and received lecture fees from NovoNordisk, MSD and Sanofi-Aventis. Laurent Bequemont has close family member working at Sanofi-Aventis, consults for Sanofi-Aventis, Pfizer, Servier and received lecture fees from Genzyme, GlaxoSmithKline, Bristol-Myers Squibb and Merck Sharp and Dohme. Khalil El Asmar, Séverine Trabado, Albane Vievard, Céline Verstuyft, Romain Colle and Emmanuelle Corruble have nothing to declare.

Dual inhibition using cabozantinib overcomes HGF/MET signaling mediated resistance to pan-VEGFR inhibition in orthotopic and metastatic neuroblastoma tumors.

MET is expressed on neuroblastoma cells and may trigger tumor growth, neoangiogenesis and metastasis. MET upregulation further represents an escape mechanism to various anticancer treatments including VEGF signaling inhibitors. We developed in vitro a resistance model to pan-VEGFR inhibition and explored the simultaneous inhibition of VEGFR and MET in neuroblastoma models in vitro and in vivo using cabozantinib, an inhibitor of the tyrosine kinases including VEGFR2, MET, AXL and RET. Resistance in IGR-N91-Luc neuroblastoma cells under continuous in vitro exposure pressure to VEGFR1-3 inhibition using axitinib was associated with HGF and p-ERK overexpression. Cabozantinib exhibited anti-proliferative effects in neuroblastoma cells and reduced cell migration in vitro as measured by phase-contrast with IncuCyte system. In vivo, an enhanced number of animals with IGR-N91-Luc metastases was noted following axitinib treatment as compared to control animals. Orally administered cabozantinib per gavage at 30 and 60 mg/kg/day significantly inhibited tumor growth of orthotopic adrenal IGR-N91-Luc and metastatic IMR-32-Luc xenografts. Antitumor activity was associated with decreased vascularization, inhibition of p-SRC and induction of apoptotic cell death. Activation of the HGF-mediated MET pathway is involved in escape to selective VEGFR inhibition in neuroblastoma suggesting combined inhibition of MET and VEGFR signaling to reduce secondary resistance and enhanced invasiveness.

Regorafenib: Antitumor Activity upon Mono and Combination Therapy in Preclinical Pediatric Malignancy Models.

The multikinase inhibitor regorafenib (BAY 73-4506) exerts both anti-angiogenic and anti-tumorigenic activity in adult solid malignancies mainly advanced colorectal cancer and gastrointestinal stromal tumors. We intended to explore preclinically the potential of regorafenib against solid pediatric malignancies alone and in combination with anticancer agents to guide the pediatric development plan. In vitro effects on cell proliferation were screened against 33 solid tumor cell lines of the Innovative Therapies for Children with Cancer (ITCC) panel covering five pediatric solid malignancies. Regorafenib inhibited cell proliferation with a mean half maximal growth inhibition of 12.5 µmol/L (range 0.7 µmol/L to 28 µmol/L). In vivo, regorafenib was evaluated alone at 10 or 30 mg/kg/d or in combination with radiation, irinotecan or the mitogen-activated protein kinase kinase (MEK) inhibitor refametinib against various tumor types, including patient-derived brain tumor models with an amplified platelet-derived growth factor receptor A (PDGFRA) gene. Regorafenib alone significantly inhibited tumor growth in all xenografts derived from nervous system and connective tissue tumors. Enhanced effects were observed when regorafenib was combined with irradiation and irinotecan against PDGFRA amplified IGRG93 glioma and IGRM57 medulloblastoma respectively, resulting in 100% tumor regressions. Antitumor activity was associated with decreased tumor vascularization, inhibition of PDGFR signaling, and induction of apoptotic cell death. Our work demonstrates that regorafenib exhibits significant antitumor activity in a wide spectrum of preclinical pediatric models through inhibition of angiogenesis and induction of apoptosis. Furthermore, radio- and chemosensitizing effects were observed with DNA damaging agents in PDGFR amplified tumors.